Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive sub-type of non-Hodgkin lymphoma accounting for 30 to 40% of cases. Among DLBCLs the activated B-cell (ABC) subtype is the most resistant to the current standard of care and has the poorest prognosis with only a 35% 5-year survival rate. Identification of underlying genetic and functional abnormalities has provided compelling evidence that MALT1 is a critical effector enzyme of tumor growth and survival forming a critical node between the two major constitutively active NF-8B signaling pathways BCR and TLR. Importantly, the MALT1 protease activity in particular has been shown to be essential for survival of ABC-DLBCL cells suggesting that small molecule MALT1 inhibitors may be effective targeted therapy for this subtype of DLBCL. Furthermore, MALT1 is an attractive enzyme for ABC-DLBCL therapy as proteases are highly 'druggable' targets and MALT1-null animals are healthy aside from defects in B and T cell function suggesting that selective MALT1 inhibitors are tractable and unlikely to exert any significant deleterious effects in humans. We recently reported on MI-2, one of only two reported MALT1 inhibitor classes. MI-2 inhibits growth of ABC-DLBCL cell lines and xenografts dependent on MALT1 while exhibiting little to no effect on MALT independent cell lines. Furthermore, MI-2 inhibits the proliferation of primary human DLBCLs ex vivo and is non-toxic to mice. Overall our results lend considerable pharmacological validation of MALT1 as a therapeutic target in ABC-DLBCL. To further assess the potential of MALT1 as a target in ABC-DLBCL and the translational potential of our 'lead' series we propose to develop more potent and selective MALT1 inhibitors with improved pharmacokinetic properties and an acceptable in vitro safety profile. The developed inhibitors will be evaluated for efficacy against ABC-DLBCL in murine models and against primary human samples; top compounds will be further evaluated in a two-week rat toxicology experiment. A multi-disciplinary team has been assembled to perform the medicinal chemistry (Nathanael Gray and Sara Buhrlage, Dana-Farber Cancer Institute), biochemistry and structural biology (Hao Wu, Boston Children's Hospital), and cell biological and pharmacological models of DLBCL (Ari Melnick, Weill Cornell Medical College) required to pharmacologically interrogate MALT1 in ABC-DLBCL.